Not applicable.
1. Field of the Invention
The present invention generally relates to methods for treating inflammed tissue. More particularly, the invention relates to stents for treating vessels and other annular organs that are capable of being selectively heated by an external source of radiation and of transferring that heat to surrounding tissue. The invention also relates to methods of making and using such heating stents to apply low-level heat to inflammed tissue
2. Description of Related Art
Coronary artery disease is a leading cause of death in industrialized countries. It is manifested by athersclerotic plaques, which are thickened areas in vessel walls. A plaque is an accumulation of cholesterol, proliferating smooth muscle cells and inflammatory cells covered by cellular secretions of collagen that form a cap over the plaque in the vessel wall. Macrophages migrate into and accumulate in a plaque causing inflammation. Inflamed plaques are most susceptible to ruptures and the formation of blood clots. Falk, E. (1995).
Atherosclerotic plaques are thought to develop in response to irritation or biochemical damage of the endothelial cells that line blood vessel walls. Agents that are known to damage these cells include cigarette smoke, high serum cholesterol (especially in the form of oxidized low density lipoprotein), hemodynamic alterations (such as those found at vessel branch points), some viruses (herpes simplex, cytomegalovirus) or bacteria (e.g., Chlamydia), hypertension, and some plasma hormones (including angiotensisn II, norepinephrine) and homocysteine. Atherosclerotic plaques grow slowly over many years in response to the cumulative injury of endothelial cells. Ross (1993), Berliner (1995).
Typically, several dozen plaques are found in arteries afflicted with this disease. It is the rupture of these plaques that brings about the terminal stage of the disease. The rupture causes a large thrombus (blood clot) to form on the inside of the artery, which may completely occlude the blood flow through the artery, thereby injuring the heart or brain. Falk, E. (1995).
In most cases of terminal coronary artery disease, only one of several plaques ruptures. Rupture typically is caused by inflammatory cells, primarily macrophages, that lay beneath the surface collagen layer of the plaques. These cells release enzymes that tend to degrade the cap. Once a plaque ruptures, blood clots are formed and it is these clots that are believed to be responsible for over one half of all heart attacks and stokes. Falk, E. (1995); Buja (1994).
Techniques have been developed to identify those plaques that are most likely to rupture because of inflammation. See U.S. patent application Ser. No. 08/717,449, which is specifically incorporated by reference herein. The most common treatment for these plaques is percutaneous transluminal coronary angioplasty (PTCA), e.g., balloon angioplasty. Frequently, however, injury to the vessel wall and disruption of the plaque core occur during restoration of vessel patency. The rapid proliferation of smooth muscle cells in response to damage and inflammation induced in the intimal and medial layers of the vessel wall occurs as part of the body""s attempt to heal the xe2x80x9cwoundxe2x80x9d to the vessel. This leads to neointimization and remodeling of the vessel wall and restenosis. Restenosis is defined as the reclosure of a previously stenosed and subsequently dilated peripheral or coronary vessel. Blood clots may form as a result of the spillage of plaque contents and due to triggering of the natural clot-forming cascade of the blood, further contributing to restenosis at the treatment site. Within weeks to months after PTCA, many individuals develop restenosis at the angioplasty site. Various approaches to balloon catheter angioplasty have been introduced, however each has failed at preventing post-angioplasty restenosis. Some of these include atherectomy devices, laser and thermal ablative devices and stents, examples of which are well known by those working in the field.
Apoptosis
It is clear that in many cases balloon angioplasty causes cellular injury and only temporarily eliminates the danger from an inflamed plaque until the advent of a secondary inflammatory response. Casscells (1994).
It has been shown that macrophages have a life span of only about a week or two in the vessel wall. Katsuda (1993). Typically, monocytes enter the atherosclerotic plaque, divide once, and contribute to plaque development by their ability to oxidize low density lipoprotein cholesterol and to release factors which cause smooth muscle proliferation and angiogenesis. The cells then undergo apoptosis, which is an active process of programmed cell death. This process differs from necrosis in that apoptosis requires the expenditure of energy, and the synthesis of new RNA and proteins in all but the inflammatory cells, the active cleavage of DNA and the shrinkage and involution of the cell with very little inflammation. Steller (1995); Nagata (1995); Thompson (1995); Vaux (1996).
Apoptosis is a form of programmed cell death in which the dying cells retain membrane integrity and are rapidly phagocytosed and digested by macrophages or by neighboring cells. It occurs by means of an intrinsic cellular suicide program that results in DNA fragmentation and nuclear and cytoplasmic condensation. The dead cells are rapidly cleared without leaking their contents and therefore little inflammatory reaction follows. It can be induced by the withdrawal of growth factors and to some extent by factors which can also cause necrosis such as extreme lack of oxygen or glucose, heat, oxidation and other physical factors.
Previously no method was known for selectively inducing apoptosis in macrophages or other inflammatory cells in a blood vessel without also inducing apoptosis in beneficial endothelial cells. Known methods for inducing apoptosis were systemic, including treatments with chemicals and elevated temperatures. Such methods are not useful as therapeutic methods because of the risk that apoptosis will develop in healthy tissue.
A number of studies have shown that heat can induce programmed cell death. Kunkel (1986) have found that indomethacin inhibits macrophage synthesis of prostaglandin but enhances macrophage production of TNF-I, which suggests that heating may have advantages over indomethacin as an anti-inflammatory treatment. Preventing the synthesis of prostaglandin, which serve as feedback inhibitors of macrophage function, limits the anti-inflammatory utility of indomethacin and presumably other inhibitors of cyclooxygenase. Field and Morris (1983) surveyed many cell types and found that the time needed to kill cells at 43xc2x0 C. varied from four minutes in mouse testis, to 32 minutes in rat tumor in vivo, to 37 minutes for mouse jejunum, to 75 minutes for rat skin, 210 minutes for mouse skin and 850 minutes for pig skin. Numerous other cell types were also studied. They observed that, above 42.5xc2x0 C., an increase of 1xc2x0 C. produces a similar effect as doubling the duration of heat exposure. Wike-Hooly (1984) found that a low pH enhanced hyperthermic cell killing, as did a low glucose or insulin exposure and that nitroprusside also increased the cell mortality caused by hyperthermia. Raaphorst (1985) and Belli (1988) studied Chinese hamster lung fibroblasts and found that 45xc2x0 C. heat and radiation were synergistic in cell killing. Raaphorst (1985) also found S-phase to be heat-sensitive and least radiosensitive, while in G1 and G2 the opposite was true. Klostergard (1989) found that cytotoxicity of macrophages was decreased by heating to 40.5xc2x0 C. for 60 minutes. Westra and Dewey (1971) found that in CHO cells S phase was more sensitive to heating to 45.5xc2x0 C. than was G1 phase. M phase was intermediate. In contrast, radiation killed cells preferentially in phases G1 and M1. Fifty percent of asynchronous (cycling) CHO cells were killed by a 20 minute heat treatment at 43.5xc2x0 C. Freeman (1980) found that the sensitivity of CHO cells to 41xc2x0 C. to 45.5xc2x0 C. was increased with acidosis and that thermotolerance was induced by exposure to 42xc2x0 C. for 250 minutes. Haverman and Hahn (1982) used an inhibitor of oxidative phosphorylation and found that CHO cells were thereby more prone to heat-induced death using 43xc2x0 C. for one hour. Preheating, however, led to tolerance. These experiments could not determine whether hyperthermia increased ATP utilization or inhibited its synthesis. Gerweck (1984) found that CHO cells were more easily killed by 44xc2x0 C. (20% died after a 15-minute exposure) when ATP was depleted by hypoxia and hypoglycemia, but neither condition alone had an effect. Lavie (1992) found that peritoneal macrophages from older mice tend to die at 42.5xc2x0 C. for 20 minutes but not macrophages from younger mice. Papdimitriou (1993) found that most peritoneal murine macrophages undergo apoptosis with a five-hour exposure to 41xc2x0 C., but few entered apoptosis at 30xc2x0 C. Most circulating monocytes did not undergo apoptosis at 41xc2x0 C., with a five-hour exposure. Mangan (1991) reported that TNF alpha and interleukin-l beta prevent macrophage apoptosis. Chen (1987) reported that heat in the range of 41xc2x0 C. to 43xc2x0 C. stimulated macrophage production of prostaglandins. Prostaglandins serve to suppress macrophage production and phagocytosis. Heat did not decrease prostaglandin release from tumor cell line or from fibroblasts. They found that macrophage death began at 41xc2x0 C. with a four-hour exposure. A six-hour exposure to 43xc2x0 C. killed half the macrophages. Ensor (1995) found no macrophage cell death after six hours at 40xc2x0 C., (vs. 37xc2x0 C.) but at 43xc2x0 C. only 4% of cells were viable at six hours. O""Hara (1992) found that bone marrow macrophages survive 15 minutes at 45xc2x0 C. if they have been preheated for 110 minutes to 42.5xc2x0 C.
Fouqueray (1992) found that exposing rat peritoneal macrophages to 39xc2x0 C. to 41xc2x0 C. for 20 minutes decreased synthesis of IL-1 and TNF-I. Circulating monocytes were less sensitive to heat than glomerular or peritoneal macrophages. This degree of heating did not kill the macrophages. Hamilton (1995) found that the cancer drug bleomycin blocked expression of HSP-72 in human alveolar macrophages in response to exposure to 39.8xc2x0 C. This was a relatively specific effect since there was no change in overall protein synthesis and, moreover, the effect appeared to be post-transcriptional, since there was no change in mRNA levels for HSP-72. The bleomycin exposure did not cause much necrosis, but it caused marked DNA fragmentation characteristic of apoptosis. Wang (1995) found that induction of HSP-72 prevented necrosis in human endothelial cells exposed to activated neutrophils. The activated neutrophils caused necrosis of endothelial cells that had been exposed to 30 to 60 minutes of heat shock at 42xc2x0 C., an exposure which by itself did not induce necrosis or apoptosis. Wang (1997) found that endothelial cells did not go to apoptosis with a 45-minute exposure to 42xc2x0 C. or with exposure to TNF-I, but exposure to both did trigger apoptosis. TNF-I resulted in generation of reactive oxygen species, which the authors believe may be required, together with heat shock, to induce apoptosis in endothelial cells. Kim (1997) found that nitric oxide protected cultured rat hepatocytes from TNF-I induced apoptosis by means of inducing HSP-70. Belli (1963) observed that heating enhances cell susceptibility to radiation killing.
Cytokines are also known to influence apoptosis in macrophages and other leukocytes. William (1996) found that apoptosis in neutrophils was promoted by heat, TNF-I, or endotoxin but inhibited by LPS, GMCSF and IL-2. Biffl (1996) found that IL-6 also delayed neutrophil apoptosis. Prins (1994) found in human fat tissue explants adipocytes underwent apoptosis within 24 hours of a 60-minute exposure to 430 C. and then underwent phagocytosis, suggesting that at least some macrophages survived longer than some adipocytes. O""Hara (1992) showed that granulocyte-macrophage precursors take longer (Txc2xd=36 min.) to become heat-tolerant than do stem cells or erythrocyte precursors from bone marrow. Verhelj (1996) found that 50 percent of confluent, nondividing, bovine aortic endothelial cells underwent apoptosis by 12 hours at 43xc2x0 C., versus 41xc2x0 C. for dividing human monoblastic leukemia of the U937 line, but this difference could well be attributable to the difference in age of the cells, cycling rate or species. D. Elkon and H. E. McGrath (1981) presented some evidence that granulocyte monocyte stem cells do not take as long as other cells to be killed at a temperature of 42.5xc2x0 C. Blackburn (1984) reported that circulating monocyte precursors are more sensitive to heat than are those from bone marrow. Kobayashi (1985) reported that granulocyte-macrophage progenitor cells were more sensitive to 60 minutes at 42xc2x0 C. when the marrow was regenerating (during cell division) than when it was stationary, but this is a finding in all cell types. Cohen (1991) found no difference in heat tolerance of epithelial cells and airway macrophages, as measured by immediate release of LDH and chromium-51.
A number of studies have examined the relationship between heat shock and cell killing. Nishina (1997) found that the stress-activated protein kinases (also known as the Jun N-terminal kinases) are activated in response to heat shock and other cell stresses. A knockout of one of these genes (SEK-1) resulted in fewer CD4+, CD8+ thymocytes. Pizurki and Polla (1994) found that cAMP increased synthesis of heat-shock proteins in heated macrophages. Reddy (1982) found that heat shock of murine macrophages increased their production of superoxide but did not change their production of hydrogen peroxide or their microbicidal activity. Sivo (1996) found that heat shock acted in a fashion similar to glucocorticoids in inhibiting mouse peritoneal macrophages and increased the transfer of glucocorticoid receptors to the nucleus. Snyder et. al (1992) found that mouse peritoneal macrophages synthesized heat-shock proteins (HSPs) maximally after a 12-minute exposure to 45xc2x0 C.; HSPs were only found two to six hours after heat treatment. They found no HSP-70 at 42xc2x0 C. or 43xc2x0 C. At 2 and 24 hours after heating, phagocytosis was normal. They did not mention whether macrophages entered apoptosis with this treatment and that the same treatment (12 minutes at 45xc2x0 C.) decreased TNF alpha and IL-1 RNA synthesis in mouse peritoneal macrophages. Pizurki et. al (1994) reported that circulating human monocytes express HSPs two hours after 20 minutes of exposure at 45xc2x0 C. and that HSP expression was enhanced in the presence of cAMP and unaffected by indomethacin.
A number of studies have shown that heating and chemical treatments change the activity of immune cells. Chen (1987) found that heating murine macrophages to 41xc2x0 C. to 43xc2x0 C. for one hour caused them to synthesize and release prostaglandins of the E type. Fouqueray (1992) found that a 20-minute exposure of rat peritoneal macrophages to 39xc2x0 C. to 41xc2x0 C. decreased synthesis of tumor necrosis factor alpha and interleukin-1 within two hours, but monocytes circulating in the blood were less sensitive to heating than were the tissue macrophages. Ribeiro (1996) confirmed that heat exposure decreases macrophage release of TNF alpha both in vitro and in vivo. Kunkel (1986) showed that indomethacin inhibited lipopolysaccharide (LPS)-induced synthesis of prostaglandins by macrophages (and inhibited heat-induced PGEs (Chen, 1987) but enhanced macrophage production of TNF-I in response to LPS. Morange M. (1986) found that HSPs were induced at lower temperatures when cells were exposed to interferonalpha and interferon-beta. Ensor (1995) reported that exposing a macrophage cell line to 40xc2x0 C. for 30 minutes prevented (within six hours) synthesis and release of TNF-I in response exposure to LPS. The half-life of TNF-I mRNA was shortened. There was no change in the levels of MRNA for GAPDH, xcex8-actin or IL-6. HSP-72 was increased at 43xc2x0 C. The same authors previously showed that in human macrophages TNF expression was suppressed at 38.5xc2x0 C., but HSP-72 was increased only above 40xc2x0 C. Papadimitriou showed that macrophage apoptosis was minimal at 39xc2x0 C. but substantial at 41xc2x0 C.
Although the cellular phenomenon of apoptosis has been studied in some detail in tissue culture, no studies have been directed toward developing that technique for the treatment of inflammation. New methods are needed for treating inflamed body tissues and in particular to the treatment of atherosclerotic plaques to prevent rupture. Such methods should not induce an inflammatory response and should be capable of eliminating or neutralizing macrophages or other inflammatory cells without damaging blood vessel walls. Novel methods for selectively inducing apoptosis are also needed. Such methods will be useful in preventing the rupture of atherosclerotic plaques and therefore reduce the risk of death from myocardial infarction or stroke.
Stents
An intravascular stent is typically an expandable stainless steel wire mesh cylinder that is transported in compressed form into the lumen of a vessel by means of a catheter. Once the desired site is reached, the stent is deployed so that it presses against the vessel wall to mechanically hold the lumen open. Aside from metals and memory metal alloys, plastics have also been used to form stents. Over the last decade, cardiovascular stent implantation has become a preferred mode of treatment following angioplasty and atherectomy procedures, and is now widely used in interventional centers throughout the United States and other countries. While various stent devices have almost always improved short-term results in vessel patency, at the present time it is not yet determined whether any of the many stent designs and materials have significant advantages over the others. For example, some stents penetrate the plaque, whereby a gruel-like material is extruded through the strut lattice, provoking an intense thrombotic and inflammatory response. Other stent designs merely compress the plaque mass with less disruption of the plaque core. The long-term outcomes with presently available stents, particularly their ability to inhibit restenosis at the site of implantation, are still to be determined. (See Topol et al. 1998; Oesterle et al. 1998). Particular problems that have been associated with stents include thrombus formation and cellular overgrowth. During stent placement the blood vessel wall can be disturbed or injured, and thrombosis often results at the injured site, causing stenosis (narrowing) or complete blockage of the vessel. The basic principle that extensive medial injury leads to more inflammation is common to all coronary interventions. Rupture of a necrotic core, with exposure of the plaque contents, appears to be a potent stimulus for inflammation and profuse proliferation of smooth muscle cells (Oesterle et al., 1998).
Stents that remain in place in a patient for an extended period of time also provide a setting for thrombus formation and for overgrowth of vascular smooth muscle cells on the device itself, which contributes further to stenosis, sometimes referred to as xe2x80x9cin-stent restenosis.xe2x80x9d For example, P. W. Serruys has shown (in the xe2x80x9cHandbook of Coronary Stentsxe2x80x9d Martin Dunitz Ltd., London 1997, in FIG. 1.3 on p. 2) by an electron microscope scan of a wall stent at three days post-implantation that deposits of leukocytes, platelets and thrombus adhere to the wire mesh, and that there is some protrusion of the vessel wall into the lumen. These deposits are thrombotic and mitotic, eventually causing neointimal proliferation and thombotic regions. As a result, the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, and stroke, depending on the placement of the stent.
In addition to the plaque extruding tendency of lattice-like stent designs, the metal composition and other characteristics of the stent surface are also believed to be important factors for the performance of an implanted stent. It is well established that stainless steel implants such as pacemakers tend to release chromium and nickel ions, which can destroy or damage certain enzymes and proteins and can exacerbate allergies to these metals.
Non-metallic stents have also been used for endovascular support. These devices are generally cylindrical structures made up of a sheet or sleeve of resilient, elastic material which can be cured or hardened following delivery of the stent to a selected region of a vessel. For example, U.S. Pat. No. 5,100,429 (Sinofsky) discloses an endovascular stent having a tubular body formed as a rolled sheet of a biologically compatible material having a cross-linkable adhesive material between overlapping portions of the rolled sheet. U.S. Pat. No. 5,591,199 (Porter) is for a vascular stent made up of a biocompatible fibrous material that is coated or filled with a curable material so that the fiber composite can be shaped and cured to maintain the shape. U.S. Pat. No. 5,282,848 (Schmitt et al.) discloses a self-supporting stent having a continuous uniform surface made up of a woven synthetic material. U.S. Pat. No. 5,814,063 (Freitag) describes a method of embedding the supporting metal stent structure in a cylindrical elastomeric casing such as silicone. However, a potential problem with the sleeve or sheet type of stent is that blood may not adequately circulate to the vessel wall adjacent the stent. Fully covering the endothelium of the vessel wall is also undesirable as the endothelium plays an essential role in biologic activity of the coronary artery, such as fibrinolysis and vasodilation.
Application of a biocompatible coating to a metal stent is currently the most widely-used technique for avoiding problems encountered with bare metal stents. For example, the DIAMOND(trademark) stent produced by the Phytis Company of Hamburg, Germany has been shown to avoid these metal diffusion problems. Smooth coatings can significantly reduce the surface roughness of the bare metal surface to improve hydrodynamic behavior and to deter adsorption of proteins, which leads to thrombus formation. The phosphorylcholine-coated stent manufactured by Biocompatibles Ltd., Farnham, Surrey, UK, is an example of a more hemocompatible metal-based stent.
Stent-coating materials that have been used to decrease the inherent thrombogenicity of stents and/or reducing in-stent restenosis include the following synthetic substances: polyurethane, segmented polyurethaneurea/heparin, poly-L-lactic acid, cellulose ester, polyethylene glycol and polyphosphate ester. Thrombus inhibitors and other therapeutic agents have also been incorporated into the fiber matrix of non-metallic stents, or attached to a biocompatible coating that encapsulates a stent. Some of the naturally occurring substances that have been described as biocompatible or therapeutic coatings for stents include: collagen/laminin, heparin, fibrin, phosphorylcholine, AZ1 (monoclonal antibody directed against rabbit platelet integrin xcex1IIIbxcex23) absorbed to cellulose, and AZ1/UK (monoclonal antibody directed against rabbit platelet integrin xcex1IIIbxcex23/urokinase conjugate) adsorbed to cellulose. (Topol et al., 1998).
U.S. Pat. No. 5,749,915 (Slepian) describes a method of forming a biocompatible polymer coating on a vessel wall by providing a biocompatible polymeric material that is non-fluent at body temperature, yet which becomes fluent at an elevated temperature. The material is heated to render it fluent, contacted with a tissue surface to be xe2x80x9cpavedxe2x80x9d, and allowed to cool, thereby providing a non-fluent biocompatible polymeric covering on the vessel wall.
Therapeutic stents have also been described as vehicles for prolonged local drug administration, as means for delivery of gene therapy to cells of the arterial wall, and as carriers of viable endothelial cells to passivate the stent surface (See Topol et al., 1998). U.S. Pat. No. 5,674,192 (Sahatjian, et al.) describes a drug-carrying balloon catheter and stent with a polymer coating such as a swellable hydrogel incorporating the drug. The expandable portion of the catheter can be adapted for application of heat to the polymer material to control the rate of administration. The polymer is meltable and the release of the polymer is aided by the application of heat.
U.S. Pat. No. 5,906,636 (Casscells, et al.) discloses use of an endolumenal stent to gently heat an inflamed atherosclerotic plaque for reducing inflammation and/or inducing apoptosis in plaque cells as a means for preventing or delaying restenosis after angioplasty or stenting.
The use of electromagnetic energy, including microwave, radio frequency (RF), coherent (laser), ultraviolet (UV) and visible-spectrum light energy, have been used in various angioplasty and atherectomy devices, endeavoring to destroy plaque without harming the vessel wall. For example, U.S. Pat. No. 5,057,106 (Kasevich) discloses the use of microwave energy for heating atherosclerotic plaque in the arterial wall in combination with dilation angioplasty. U.S. Pat. No. 4,807,620 (Strul) and U.S. Pat. No. 5,087,256 (Taylor) provide representative examples of atherectomy or angioplasty devices that convert electromagnetic RF energy to thermal energy. U.S. Pat. No. 5,053,033 (Clarke) describes the use of an UV laser to inhibit restenosis by irradiation of smooth muscle cells with non-ablative cytotoxic light energy. U.S. Pat. No. 4,997,431 (Isner); U.S. Pat. No. 5,106,386 (Isner); U.S. Pat. No. 5,026,367 (Leckrone); U.S. Pat. No. 5,109,859 (Jenkins); and U.S. Pat. No. 4,846,171 (Kauphusman) each disclose the use of laser light transmitted via an optical fiber or conduit to reduce tissue mass or remove arterial plaque by ablation. U.S. Pat. No. 4,878,492 (Sinofsky) and U.S. Pat. No. 4,779,479 (Spears) describe the use of nonablative laser light energy of sufficient wattage to heat the arterial plaque during a conventional PTCA dilation procedure in order to fuse fragmented plaque and coagulate trapped blood. Typically, these kinds of devices fail to distinguish normal vessel wall from atherosclerotic plaque, however.
Stent-type devices have also been employed for thermal therapy of various annular organs and vessels, almost all of which are directed at inhibiting or killing cancer cells and typically generate temperatures in the cell necrosing range and beyond. Goldberg (1997) has described one type of heating stent for applying RF energy to indwelling metallic stents to induce transluminal coagulative necrosis. Another type of heating stent is disclosed in Japanese Pat. No. 6063154 (Koji et al.), which describes a heat generating stent for placement in an annular organ for tumor treatment. The hollow stent is made of a thermosensitive magnetic material that is heated by an external high-energy, alternating magnetic field. Similarly, Japanese Pat. No. 6063155 (Koji et al.) describes the application of a thermosensitive medicine-containing polymer to the thermosensitive magnetic stent to provide temperature-controlled treatment of an annular organ or vessel.
However, problems may arise when the body is exposed to a high electromagnetic field. For instance, other implanted metallic objects in the body, such as pacemakers, defibrillators or cardiovascular stents, may malfunction or heat up dangerously if exposed to a strong electromagnetic field. Additionally, the effects of high magnetic fields on biological tissue are still not completely understood. Such fields may cause ionization of some biomolecules and cellular damage. Another disadvantage of techniques requiring high-energy magnetic field production is that they require facilities that are costly to maintain and are not widely available to the medical community.
Other methods of heating vessels or other annular organs, such as resistive heating of a fluid-filled balloon catheter, for example, which require passage of electricity to the body are inherently difficult to control and can also present a hazard to the patient. Moreover, all of the conventional intravascular heating methods are invasive and catheter-based.
Ultrasound (US) is another energy source that is applied to the body and is particularly well known for its diagnostic imaging utility, particularly in monitoring fetal development and for echocardiography in the diagnosis of cardiac conditions. Ultrasound is generally considered to be a safe diagnostic and therapeutic tool when employed clinically, and the beneficial therapeutic effectsxe2x80x94both thermal and non-thermalxe2x80x94of ultrasound in physical therapy are widely recognized, particularly for wound healing and in reducing pain. (See, for example, McDiarnid, et al. 1987). Therapeutic use of ultrasound for cardiovascular-related conditions include, for example, enhancement of thrombolysis by transcutaneous ultrasound treatment, as described by Luo et al. (1998). Intravascular ultrasound (IVUS) imaging is currently being used to assist stent implantation (Oesterle, 1998). U.S. Pat. No. 5,836,896 (Rosenschein) describes a method of inhibiting restenosis by applying intravascular ultrasonic energy to smooth muscle cells of the vessel wall in order to inhibit the migration and adherence of smooth muscle cells. This method, however, takes advantage of the non-thermal effect of ultrasound to produce cavitation within a vessel in a region of angioplasty or atherectomy injury.
Diagnostic and therapeutic uses of ultrasound are based on the fact that almost every substance has a characteristic acoustic impedance, which is based on the speed at which ultrasound waves travel in that substance, or medium. Ultrasound waves may move, or propagate, through a medium more or less freely, or they can be absorbed, reflected or scattered by the molecules of the medium. It is the relative contribution of each of these factors that determines the speed at which ultrasound will travel in a given medium. Resistance to movement due to absorbance, reflectance or scattering is generally termed xe2x80x9cacoustic impedance.xe2x80x9d The acoustic impedance of a substance is equal to the product of the density of the substance and the speed of sound therein.
Accordingly, each tissue in the body will absorb a certain percentage of the energy from ultrasound waves that propagate through it. Ultrasound travels at a speed of about 1.5xc3x97105 cm/s in most soft tissues. When an ultrasound wave is absorbed, or partly absorbed by tissue, the associated kinetic energy is converted to thermal or heat energy, raising the temperature of the tissue a corresponding amount. At the interface between two acoustically different tissues, such as bone and soft tissue in the body, even more heat is generated by the ultrasound due to reflectance by the denser medium. Reflectance can produce xe2x80x9cstanding waves,xe2x80x9d as discussed by Roy Williams (1987). Recent tests of the effects of ultrasound irradiation on non-living porcine tissue, when placed on both metal and plastic surfaces, were performed by Robertson et al. (1995). The results of those studies showed a markedly higher maximum temperature increase in the tissue, and a significantly greater initial rate of heating, when the tissue was on the metal surface rather than on the plastic surface. Ultrasound, particularly pulsed high intensity ultrasound, can quickly cause excessive heating and even burning of soft tissue in contact with bone or another acoustically reflective object, such as a conventional metal stent, unless the conditions are carefully controlled.
Even though ultrasound has been in use both diagnostically and therapeutically for over a decade, and its beneficial results have been attributed to both thermal and non-thermal effects, there has been little research on the effect of treatment dosage on the extent of tissue heating. (See, for example, Kimura et al. 1998). Barnett et al. (1994) have reported that exposure to even diagnostic levels of low intensity ultrasound produce significant temperature increases in vivo, specifically at interfaces between bone and soft tissue. Fan and Hynynen (1992) have reported the effect of wave reflection and refraction at soft tissue interfaces during ultrasound hyperthermia treatments. A temperature increase of more than 5xc2x0 C. has been reported with diagnostic ultrasound equipment, using either pulsed-wave or continuous-wave low intensity ultrasound for tissue close to bone S. Barnett (1998). Wells (1992)) focuses on the biological effects due to heating by diagnostic ultrasound, with particular reference to the monitoring of prenatal development of animals.
Today, ultrasound thermal therapy is only used for heat delivery to large volumes of tissue, such as tumors, to burn sites of internal bleeding to achieve coagulation and clot formation, and for physical therapy. High intensity focused ultrasound is effective for heating cancerous tissue, typically increasing the temperature of the target tissue by about 10-20xc2x0 C. and often up to about 85xc2x0 C. High intensity ultrasound is also used to stop bleeding, in lithotripsy procedures, and for deep surgery. For example, the SONABLATE(trademark) acoustic ablation device (Focus Surgery, Inc., Indianapolis, Ind.) is reported to permit bloodless noninvasive surgery in all parts of the body. Generally, in tissues where heat removal by blood flow or by conduction is significant, higher energy pulsed beams of focused ultrasound are sometimes employed in order to more quickly achieve the desired level of heating at a target site. Thermal therapy devices have particular difficulty in establishing and maintaining the desired therapeutic temperature in highly perfused tissues. Also, blood flowing through an artery makes it very difficult to heat a region of the vessel to a desired temperature. Oftentimes, considerable damage to intervening tissue also occurs as a consequence of the higher energy ultrasound required with existing ultrasound thermal treatment methods.
Conventional metal stents, when exposed to a focused high intensity ultrasound beam may cause damage or burning of the surrounding cardiovascular tissue due to reflectance by the metallic surface of the stent. It would be desirable to have safer stents that could avoid at least some of the problems typically encountered with conventional stents, as described above. A non-invasive way to apply thermal therapy intravascularly would be particularly advantageous over the existing catheter-based techniques. It would be even more desirable to have a way to utilize existing ultrasound technology to achieve controlled heating of stents for particular therapeutic or diagnostic applications, while avoiding inadvertent or excessive heating and damage to intervening or non-targeted body tissue.
The present invention provides methods that can be used to treat inflammation in body tissues and in particular to treat inflamed atherosclerotic plaques. The methods can be used to decrease or eliminate inflammation in a plaque to prevent rupture. Certain disclosed methods are particularly useful for inducing apoptosis in localized cell clusters such as the macrophages that cause an inflammatory response.
The present methods utilize localized and mild hyperthermic treatments to neutralize or preferably to induce apoptosis in inflammatory cells. Localized heat treatments avoid systemic cell damage and at the same time lead to clearance of unwanted cells without causing a secondary inflammation.
The techniques disclosed herein are useful in the treatment of inflammation. The term inflammation includes inflamed atherosclerotic plaques; restenosis; and arteritis such as that found in systemic lupus, Takayasu""s arteritis, Beheet""s syndrome, temporal (gran+cell) arteritis, myocarditis of the autoimmune etiology; arteriovenous fistulea, dialysis grafts or other vascular prosthesis. The phrase xe2x80x9ctreating inflammationxe2x80x9d also includes treating a region of a vein prior to or after balloon angioplasty, rotational or directional atherectomy, stenting or related interventions that could result in inflammation and subsequent thrombosis, acute closure or restenosis. Use of the disclosed methods on atherosclerotic plaques will reduce the chance of myocardial infarction or stroke.
Certain methods of the present invention are useful for inducing apoptosis in inflammatory cells. Inflammatory cells primarily consist of macrophages and other closely related cells of the immune system that are involved in creating inflammation. The present methods specifically contemplate inducing apoptosis in these cells with hyperthermic treatments.
Some of the present methods are directed to treating inflamed regions containing deleterious immune cells with heat in the range of 38.5xc2x0 C.-44xc2x0 C. for between about 5 minutes to 60 minutes and more typically for at least about 15 to 30 minutes. At the high end of the temperature range, from about 41xc2x0 C. to 44xc2x0 C., apoptosis is more effectively induced. Temperatures above 44xc2x0 C. are not preferred because they begin to cause cell killing through necrosis and pathways that cause secondary inflammation. Treatments at the low end of the temperature range may also be effective. For example, heating with temperatures in the range of 38.5xc2x0 C. to 40xc2x0 C., which are below those necessary to cause apoptosis on brief exposures (e.g., 15 minutes) can be used to decrease macrophage production and their release of cytokines. These temperatures are contemplated to be within the present invention. Generally, temperatures of approximately 42xc2x0 C. to 43xc2x0 C. will be used.
In patients, following routine angiography, a heat detecting probe, such as is described in U.S. pat. app. Ser. No. 08/717,449, would be used to identify lesions that are significantly hotter than the rest of the artery. Lesions at higher risk of rupture are about two degrees warmer than adjacent tissue. These lesions are detectable by heat imaging catheters consisting of any of several fibers that conduct heat, bundled into a standard coronary or other angiographic catheter ranging from 4 French to 14 French in diameter. Alternatively, a catheter with standard heat sensing electrodes on its surface could be used. In one embodiment, this would be a balloon catheter made of a compliant (soft) balloon material, so as not to damage the endothelium or disrupt the plaque itself.
Heat may be transferred to the target cells by a variety of methods. For example, heat may be transferred into an inflamed plaque in a blood vessel by means of a catheter. Several catheters are commercially available that are capable of introducing the heat required for these techniques. In addition, the catheter disclosed in U.S. patent application Ser. No. 08/717,449 can easily be equipped to emit infrared radiation by one of skill in the catheter arts. Preferred catheters are those that can deliver heat within the temperature range of 38.5-44xc2x0 C. Catheters that emit heat above about 45xc2x0 C. are not preferred because the use of such elevated temperatures may damage endothelial cells and produce a secondary inflammatory response.
Preferred embodiments of the present invention introduce heat into a region of inflamed tissue by introducing a stent into the lumen of a blood vessel or the lumen of an organ to treat inflammation in blood vessels, parenchymal smooth muscle cells or interstitial cells such as fibroblasts to prevent obstruction and/or thrombosis in the lumen. Methods for positioning stents are well known in the art. The stent is positioned in such a way as to be in thermal contact with a region of inflamed tissue. The stent is then heated. It can be heated electrically or with microwave or radio frequency radiation or other means. These heating methods can be produced from devices such as catheters within the lumen or from energy sources such as radiofrequency sources outside the body. It would be clear to one of skill in the art that the stent used in such an application must be able to transmit heat. The preferred stents are made of metal.
Although the present techniques primarily rely upon heating methods, chemical agents or radiation may also be employed to augment the effectiveness of heat treatments. For example, beta-blocking drugs, cytokines such as insulin-like growth factor, transforming growth factor B1, vascular endothelial growth factor, fibroblast growth factor, tumor necrosis factor and the like may be used to enhance the susceptibility of macrophages to heat induced apoptosis or to increase the resistance of endothelial cells to apoptosis. Effective amounts of these drugs can easily be determined by one of skill in the art.
Preferred embodiments of the present invention include ultrasonically heatable stents containing biocompatible material that heats more rapidly than does human soft tissue when a focused beam of ultrasound is directed onto the implanted stent. The disclosed methods of the invention provide a new way to invasively or non-invasively heat a tissue which is in contact with one of the coated stents of the invention by directing ultrasound at the implanted stent. The US-heatable stents of the invention also avoid at least some of the problems encountered by other US thermal therapy devices in establishing and maintaining the desired therapeutic temperature in a target tissue, particularly when one is hampered by the presence of blood perfusion in the tissue. Blood flowing through an artery makes it very difficult to heat a region of artery wall to a desired temperature. The ultrasound-absorptive coated stents of the disclosed invention achieve controlled heating for particular therapeutic or diagnostic applications, while avoiding the inadvertent or excessive heating and damage to non-targeted body tissue commonly encountered with other heating stents. The stents of the present invention, and their methods of use, advantageously employ the acoustic impedance properties of tissues and of various biocompatible polymers, among other things. Also, the xe2x80x9cdouble heatingxe2x80x9d effect that occurs due to reflectance of ultrasound by metal and at dissimilar acoustic interfaces are employed to achieve site-specific therapeutic heating of targeted regions of vessel wall.
As described in more detail below, ultrasonically heatable stents are provided which, after initial endolumenal placement, can be either invasively or non-invasively warmed to produce therapeutic levels of heat in the stent. Similarly, exemplary methods are also described for heating in situ a synthetic vascular graft.
In accordance with the present invention, an ultrasonically heatable stent is provided. The stent may be configured, or designed to maintain the patency of a human vessel, such as a coronary artery, for example. The stent contains an ultrasound-absorptive material that possesses a characteristic acoustic impedance value that is greater than that of living tissue. For the purposes of this disclosure an xe2x80x9cultrasound-absorptive materialxe2x80x9d is defined as one that absorbs an appreciable amount of the energy of an ultrasound beam whereby the temperature of the material increases. The ultrasound-absorptive material may be used to form the entire structure of the stent. Alternatively, the basic structure or framework of the stent may be made of another material, such as wire mesh, which provides the main support function of the stent and is configured to maintain patency of the vessel. In the latter embodiment, a coating of the ultrasound-absorptive material covers or overlies the stent framework and is characterized by being heatable by ultrasound at a faster rate than living soft tissue. For example, the stent coating may contain at least one US-absorptive material that has a heating rate greater than 0.86xc2x0 C. per minute when subjected to an ultrasound beam of 1 mHz frequency and 1 Watt/cm2 intensity.
Certain embodiments of the stent include a polymer that has at least one of the US-absorptive coating materials. Examples of some of the synthetic polymers that may be used are silicone, polyvinylchloride, nylon and polyurethane. Combinations of these materials may also be used in order to optimize the heating rate of the coating or to improve stability or biocompatibility of the coating. In some embodiments, the coating also includes a heatreleasable drug for local release at the site of the stent.
In an alternative embodiment of the stent of the present invention, the US-absorptive coat contains at least two layers of US-absorptive material. One of the layers covers at least one other layer, which is sandwiched between the framework and the outer layer. These two or more layers have dissimilar acoustic impedance characteristics. These two layers and their distinct interfaces work together to enhance the ultrasound-induced temperature increase of the coat when exposed to ultrasound. For example, the coating preferably has the characteristic that its temperature will increase 1-5xc2x0 C. or more in response to ultrasound irradiation at a chosen wave frequency, intensity and duration. The coating will preferably also have the characteristic that its acoustic impedance is greater than that of any intervening tissue located between the stent and an external ultrasound transducer, when said stent is situated in a vessel and ultrasonic radiation is directed toward said stent. This feature prevents tissue in the path of the ultrasonic beam from being damaged or excessively heated before the stent reaches the desired temperature.
Also provided by the present invention is a method of making the new ultrasonically heatable stents. The method includes obtaining a stent framework configured for maintaining patency of a vessel, and obtaining a biocompatible coating material characterized by having an acoustic impedance greater than that of living tissue. The coating material is applied to the stent framework in such a way that the final thickness and character of the coating permits the stent to be heatable by ultrasound at a faster rate than living tissue, as described above.
Also in accordance with the present invention, a method of making an ultrasonically heatable stent is provided. One exemplary stent is made by modifying a basic metal stent framework configured for maintaining patency of a vessel, such as a commercially available wire mesh, or zigzag stent. Over the stent framework is applied a coat or layer of a biocompatible coating material that is characterized by having an acoustic impedance greater than that of living tissue, such as that in the human body. The thickness and other characteristics of the coating are such that said the stent is heatable by ultrasound at a faster rate than living tissue. For example, a heating rate greater than 0.86xc2x0 C. per minute when subjected to an ultrasound beam of 1 mHz frequency and 1 Watt/cm2 intensity is characteristic of certain coated stents of the invention. One suitable coating material is silicone, and others include nylon, polyvinylchloride, polyurethane and phosphorylcholine, for example. Combinations of coating materials may also be used. The coating may also be applied in layers of the same or different ultrasound-absorptive material, so as to form additional acoustic interfaces. The thickness and manner of coating the stent can be varied such that the resulting coated stent is heatable by ultrasound at a faster rate than the surrounding living tissue. For example, a temperature about 1-5xc2x0 C. above ambient temperature is generated in the stent.
The present invention also provides a method of treating an atherosclerotic plaque in a living subject. An ultrasonically heatable stent, as described above, is positioned in a vessel lumen in such a way that it contacts a region of vessel wall where an atherosclerotic plaque is located. One particular kind of site in need of treatment is a stenotic plaque that has recently undergone an angioplasty or atherectomy procedure. An ultrasound transducer is advantageously positioned outside of the body of the subject, and operated to cause an ultrasonic beam to be directed onto the stent inside the vessel. For the purposes of this disclosure, the term xe2x80x9cadvantageously positionedxe2x80x9d means that the transducer is located as optimally as possible or practical for directing ultrasound waves toward a particular target. For example, one would try to avoid having hard or interfering surfaces between the transducer and the internal target. Also, positioning the transducer close to the target reduces the depth of penetration of the ultrasound waves required in order to reach the target stent. Due to the choice of ultrasonically heatable coating material covering the stent, and the optimal operation of the ultrasound system, the temperature of the stent is wanned to and maintained at about 1-5xc2x0 C. above the ambient temperature of the vessel. The ultrasonic heating of the stent is continued while the region of vessel wall contacted by the stent is heated at 38-42xc2x0 C. for a sufficient period of time to achieve the desired therapeutic goal, such as reducing post-injury inflammation or inhibiting cellular proliferation.
To further optimize the procedure, the temperature of the stent and/or the heated area of vessel wall is measured, using a conventional remote temperature monitoring method. Also, the ultrasound irradiating and temperature measuring steps can be repeated at the desired time intervals, as considered by the user to be medically beneficial. Optionally, but preferably, a microprocessor and visual display system is employed to control the operation of the ultrasound transducer and to receive, analyze and display the temperature measurements. It is also preferred in some embodiments that the ultrasonic transducer operate in the frequency and intensity ranges employed with conventional physical therapy equipment, for example, about 1-3 mHz frequency and 0.8-1.5 Watts/cm2 intensity for a sufficient time to heat and hold the stent at the desired temperature. In some embodiments, at least two transducers are arranged in an array around the body of the patient and each transducer is operated in cooperation with the others so that two or more ultrasonic beams are directed at the stent from different directions. The depth of penetration of the ultrasound signal and the amount of heating obtained with a particular stent is adjusted by tuning the frequency of the ultrasound signals. Also, the width of the beam can be narrowed by conventional means, for example an acoustic lens can be employed to focus on a desired spot, if desired. By choosing a suitable ultrasound heatable material and by advantageously positioning the transducers and adjusting and focusing the ultrasound appropriately, the temperature of the stent is more easily or quickly warmed up to and held in the desired temperature range. For example, the ultrasound heating system is adjusted so that the stent is maintained at about 1-5xc2x0 C. above ambient vessel temperature for the length of time that is needed to heat the area of vessel wall surrounding the stent at 38-42xc2x0 C.
In one embodiment of the present invention, a method of treating a site on a vessel wall includes placing an ultrasound transducer inside the esophagus, similar to the transducer placement for conventional trans-esophageal echocardiography. In some embodiments of the method of treating atherosclerotic plaque, an intravascular ultrasound transducer is positioned inside the stent instead of positioning one or more transducers outside the body. This is particularly desirable if another intravascular procedure is being performed on the patient, and the two procedures can be combined.
A method of treating a vascular injury, such as an angioplasty or atherectomy site, for inhibiting restenosis is also provided by the present invention. Similar to the method of treating an atherosclerotic plaque, an ultrasonically heatable stent is positioned along the vessel wall at a site where an angioplasty or atherectomy procedure has been recently performed. The site is subjected first to ultrasound-induced heating at 39-40xc2x0 C. to reduce post-injury inflammation. This 39-40xc2x0 C. heating can be repeated in a periodic manner in order to remove any residual or recurring inflammatory deposits on the surface of the stent, as deemed medically necessary. Subsequently, especially if restricted blood flow through said stent is detected, an ultrasound transducer may again be applied such that an ultrasonic beam is directed onto the stent. In the second phase of treatment, the stent is maintained at a temperature about 1-5xc2x0 C. above ambient vessel temperature long enough to heat any vascular tissue overgrowth and accumulated inflammatory cells to induce apoptosis. For example, the second phase heating could be 42xc2x0 C. for at least 15 minutes, to induce apoptosis in smooth muscle cells and in macrophages. If desired, the accuracy and ease of performing the procedure can be facilitated by non-invasively monitoring the temperature of the stent or the region of vessel wall. Also, a microprocessor and visual display can be used to receive, analyze and display the temperature measurements.
Another method encompassed by the present invention includes a method of reducing or eliminating a population of inflammatory cells on an implanted synthetic vascular graft, such as an arterio-venous (AV) graft, in a living subject. According to this method, an ultrasound transducer is advantageously positioned with respect to the location of the stent and is operated in such a way that an ultrasonic beam is directed on the graft. In this way the temperature of the graft, or a portion thereof, is increased about 1-5xc2x0 C. above the ambient vessel temperature. This temperature elevation is maintained for a sufficient period of time to heat the graft, or portion thereof, at a temperature of 38-42xc2x0 C. As described before, a microprocessor and monitor may be incorporated in the treatment system and ultrasound operation and temperature measurement steps may be repeated at therapeutically beneficial intervals.
Still another embodiment of the present invention provides a method of inhibiting or regressing in-stent restenosis. After an ultrasonically heatable stent of the invention is implanted into the vessel of a subject, vascular and inflammatory cells may invade or over-grow the stent, as sometimes occurs with mesh-type stents. In this case, however, an ultrasound transducer is positioned outside of the body and a low-intensity ultrasonic beam is directed at the stent. The ultrasound beam is operated in such a way that the temperature of the stent is increased to about 1-5xc2x0 C. above the ambient vessel temperature for a sufficient period of time to heat the stent at a temperature of about 42xc2x0 C. Optionally, ultrasound irradiation and temperature measurement steps are repeated at therapeutically beneficial time intervals. For example, it is desirable to heat up the stent when blood flow through the stent has become restricted, when overgrowth of vascular smooth muscle cells into the stent is believed to have occurred, or to reduce the size of blood clots in or around the stent. This procedure may also employ a microprocessor and visual display system to control the operation of said ultrasound transducer and to receive, analyze and display said temperature measurements, whereby apoptosis is induced in a population of cells of the overgrown tissue.